Review

Authors: Georgia Pitsava, Nikolaos Settas, Fabio R Faucz...

Succinate dehydrogenase (SDH) is a key respiratory enzyme that links Krebs cycle and electron transport chain and is comprised of four subunits SDHA, SDHB, SDHC and SDHD. All -deficient tumors are caused by or secondary to loss of SDH activity. As many as half of the familial cases of paragangliomas (PGLs) and pheochromocytomas (PHEOs) are due to mutations of the subunits. Gastrointestinal stromal tumors (GISTs) associated with deficiency are negative for mutations and present with distinctive clinical features such as early onset (usually childhood or adolescence) and almost exclusively gastric location. -deficient GISTs may be part of distinct clinical syndromes, Carney-Stratakis syndrome (CSS) or dyad and Carney triad (CT). CSS is also known as the dyad of GIST and PGL; it affects both genders equally and is inherited in an autosomal dominant manner with incomplete penetrance. CT is a very rare disease; PGL, GIST and pulmonary chondromas constitute CT which shows female predilection and may be a mosaic disorder. Even though there is some overlap between CT and CSS, as both are due to deficiency, CSS is caused by inactivating germline mutations in genes encoding for the SDH subunits, while CT is mostly caused by a specific pattern of methylation of the gene and may be due to germline mosaicism of the responsible genetic defect.

Topics: Adrenal Gland Neoplasms; Chondroma; Gastrointestinal Neoplasms; Gastrointestinal Stromal Tumors; Humans; Leiomyosarcoma; Lung Neoplasms; Paraganglioma; Paraganglioma, Extra-Adrenal; Pheochromocytoma; Stomach Neoplasms; Succinate Dehydrogenase

PubMed: 34012423
DOI: 10.3389/fendo.2021.680609

Authors: Tim Niehues, Sandra von Hardenberg, Eunike Velleuer...

Primary atopic disorders (PAD) are monogenic disorders caused by pathogenic gene variants encoding proteins that are key for the maintenance of a healthy skin barrier and a well-functioning immune system. Physicians face the challenge to find single, extremely rare PAD patients/families among the millions of individuals with common allergic diseases. We describe case scenarios with signature PAD. We review the literature and deduct specific clinical red flags for PAD detection. They include a positive family history and/or signs of pathological susceptibility to infections, immunodysregulation, or syndromic disease. Results of conventional laboratory and most immunological lab studies are not sufficient to make a definitive diagnosis of PAD. In the past, multistep narrowing of differential diagnoses by various immunological and other laboratory tests led to testing of single genes or gene panel analyses, which was a time-consuming and often unsuccessful approach. The implementation of whole-genomic analyses in the routine diagnostics has led to a paradigm shift. Upfront genome-wide analysis by whole genome sequencing (WGS) will shorten the time to diagnosis, save patients from unnecessary investigations, and reduce morbidity and mortality. We propose a rational, clinical landmark-based approach for deciding which cases pass the filter for carrying out early WGS. WGS result interpretation requires a great deal of caution regarding the causal relationship of variants in PAD phenotypes and absence of proof by adequate functional tests. In case of negative WGS results, a re-iteration attitude with re-analyses of the data (using the latest data base annotation)) may eventually lead to PAD diagnosis. PAD, like many other rare genetic diseases, will only be successfully managed, if physicians from different clinical specialties and geneticists interact regularly in multidisciplinary conferences.

PubMed: 39381601
DOI: 10.5414/ALX02520E

Authors: Jessica Burns, Christopher P Wilding, Lukas Krasny...

Soft tissue sarcomas (STS) are rare and diverse mesenchymal cancers with limited treatment options. Here we undertake comprehensive proteomic profiling of tumour specimens from 321 STS patients representing 11 histological subtypes. Within leiomyosarcomas, we identify three proteomic subtypes with distinct myogenesis and immune features, anatomical site distribution and survival outcomes. Characterisation of undifferentiated pleomorphic sarcomas and dedifferentiated liposarcomas with low infiltrating CD3 + T-lymphocyte levels nominates the complement cascade as a candidate immunotherapeutic target. Comparative analysis of proteomic and transcriptomic profiles highlights the proteomic-specific features for optimal risk stratification in angiosarcomas. Finally, we define functional signatures termed Sarcoma Proteomic Modules which transcend histological subtype classification and show that a vesicle transport protein signature is an independent prognostic factor for distant metastasis. Our study highlights the utility of proteomics for identifying molecular subgroups with implications for risk stratification and therapy selection and provides a rich resource for future sarcoma research.

Topics: Humans; Proteomics; Sarcoma; Hemangiosarcoma; Leiomyosarcoma; Soft Tissue Neoplasms

PubMed: 37386008
DOI: 10.1038/s41467-023-39486-2

Review

Authors: Emily S Tonorezos, Danielle Novetsky Friedman, Dana Barnea...

PURPOSE

To generate recommendations for long-term follow-up of adult survivors of heritable retinoblastoma.

DESIGN

We convened a meeting of providers from retinoblastoma centers around the world to review the state of the science and to evaluate the published evidence.

PARTICIPANTS

Retinoblastoma is a rare childhood cancer of the retina. Approximately 40% of retinoblastoma cases are heritable, resulting from a germline mutation in RB1. Dramatic improvements in treatment and supportive care have resulted in a growing adult survivor population. However, survivors of heritable retinoblastoma have a significantly increased risk of subsequent malignant neoplasms, particularly bone and soft tissue sarcomas, uterine leiomyosarcoma, melanomas, and radiotherapy-related central nervous system tumors, which are associated with excess morbidity and mortality. Despite these risks, no surveillance recommendations for this population currently are in place, and surveillance practices vary widely by center.

METHODS

Following the Institute of Medicine procedure for clinical practice guideline development, a PubMed, EMBASE, and Web of Science search was performed, resulting in 139 articles; after abstract and full-text review, 37 articles underwent detailed data abstraction to quantify risk and evidence regarding surveillance, if available. During an in-person meeting, evidence was presented and discussed, resulting in consensus recommendations.

MAIN OUTCOME MEASURES

Diagnosis and mortality from subsequent neoplasm.

RESULTS

Although evidence for risk of subsequent neoplasm, especially sarcoma and melanoma, was significant, evidence supporting routine testing of asymptomatic survivors was not identified. Skin examination for melanoma and prompt evaluation of signs and symptoms of head and neck disease were determined to be prudent.

CONCLUSIONS

This review of the literature confirmed some of the common second cancers in retinoblastoma survivors but found little evidence for a benefit from currently available surveillance for these malignancies. Future research should incorporate international partners, patients, and family members.

Topics: Follow-Up Studies; Genetic Predisposition to Disease; Global Health; Guidelines as Topic; Humans; Incidence; Retinal Neoplasms; Retinoblastoma; Risk Assessment; Risk Factors

PubMed: 32422154
DOI: 10.1016/j.ophtha.2020.05.024

Review

Authors: Nikolaos Settas, Fabio R Faucz, Constantine A Stratakis...

In this report, we review the relationship between succinate dehydrogenase (SDH) deficiency and the epigenome, especially with regards to two clinical conditions. Carney triad (CT) is a very rare disease with synchronous or metachronous occurrence of at least three different tumor entities; gastric gastrointestinal stromal tumor (GIST), paraganglioma (PGL), and pulmonary chondroma. This condition affects mostly females and it is never inherited. Another disease that shares two of the tumor components of CT, namely GIST and PGL is the Carney-Stratakis syndrome (CSS) or dyad. CSS affects both genders during childhood and adolescence. We review herein the main clinical features and molecular mechanisms behind those two syndromes that share quite a bit of similarities, but one is non-hereditary (CT) whereas the other shows an autosomal-dominant, with incomplete penetrance, inheritance pattern (CSS). Both CT and CSS are caused by the deficiency of the succinate dehydrogenase (SDH) enzyme. The key difference between the two syndromes is the molecular mechanism that causes the SDH deficiency. Most cases of CT show down-regulation of SDH through site-specific hyper-methylation of the SDHC gene, whereas CSS cases carry inactivating germline mutations within one of the genes coding for the SDH subunits A, B, C, or D (SDHA, SDHB, SDHC, and SDHD). There is only partial overlap between the two conditions (there are a few patients with CT that have SDH subunit mutations) but both lead to increased methylation of the entire genome in the tumors associated with them. Other tumors (outside CT and CSS) that have SDH deficiency are associated with increased methylation of the entire genome, but only in CT there is site-specific methylation of the SDHC gene. These findings have implications for diagnostics and the treatment of patients with these, often metastatic tumors.

Topics: Carcinogenesis; Chondroma; Epigenomics; Germ-Line Mutation; Humans; Leiomyosarcoma; Lung Neoplasms; Paraganglioma, Extra-Adrenal; Stomach Neoplasms; Succinate Dehydrogenase

PubMed: 28739378
DOI: 10.1016/j.mce.2017.07.018

Review

Authors: Sarah Watson, Nadege Gruel, François Le Loarer...

Retroperitoneal sarcomas (RPS) refer to a heterogeneous group of malignancies of mesenchymal origin developing from retroperitoneal tissues and vessels. The most frequent RPS are well differentiated/dedifferentiated liposarcomas and leiomyosarcomas, but other rare histological subtypes can be observed. Over the last decade, significant advances have been made in the pathological and molecular characterization of sarcomas. These advances have led to major changes in their diagnostic management as well as in the development of new therapeutic strategies based on tumor biology and microenvironment. This review describes the current knowledge and recent findings in the pathology and molecular biology of the most frequent RPS subtypes.

Topics: Humans; Sarcoma; Liposarcoma; Leiomyosarcoma; Retroperitoneal Neoplasms; Soft Tissue Neoplasms; Molecular Biology; Tumor Microenvironment

PubMed: 35151525
DOI: 10.1016/j.ejso.2022.02.005

Authors: Sachini Malaviarachchi, Jayantha Balawardana, Asela Senanayake...

The soft tissues are comprised of various structures and supportive tissues in the body, including muscle, connective tissues, endothelium, synovium, fat, lymphatics, and fascia. Soft tissue sarcomas may arise in any part of the body. The most common sites are the trunk and the extremities. Fibrosarcoma is the most common non-rhabdomyosarcoma soft tissue sarcoma (NRSTS) in children, in whom two peaks in incidence are observed. The first is in children younger than five years, and the second is in children and adolescents aged 10-15 years. Infantile fibrosarcoma (IFS) is almost exclusively observed in children younger than two years. Many of these sarcomas are congenital. This tumor is locally aggressive, but rarely metastatic, and occurs in the extremity in 70% of patients. A 29-year-old lady presented to the Oncology unit with the fifth recurrence of fibrosarcoma which was transformed into very vascular and high-grade leiomyosarcoma from the fourth recurrence onwards. Initially, it was diagnosed when she was two days old and radiologically diagnosed as lymphangioma. It was documented as a large lump at the right lumbar region with uniform echogenicity and was excised and the postoperative period was uneventful. At the age of 12 years, she presented with a large mass at the right lumbar region over the surgical scar and complete excision done with R0 resection. Histology revealed well-differentiated fibrosarcoma with varying sizes of fibroblasts and no alignment features. The third relapse was at the age of 27. Complete excision was done and histology reported as spinel cell tumor with the possibility of fibrosarcoma or leiomyosarcoma. It was R0 resection and adjuvant treatment was not offered. Tumour recurred over the same scar within a year. Since the tumor is very big with 10 cm craniocaudal and 9 cm wide neoadjuvant chemotherapy is given: IV doxorubicin and IV cisplatin. Surgery was performed after four cycles and found necrotic tissue only. There were no tumor tissues or any form of spindle cells. Due to the aggressive nature, there was no exact solid tumor to assess margins for recommended adjuvant radiotherapy; IMRT. Due to the delay in finding a spacer to keep the bowel away from the radiotherapy field, radiotherapy was delayed and the tumor recurred within six months. It was a radiologically very vascular tumor and she had severe neuropathy and autotoxicity and could not offer any more chemotherapy. The tumor was rapidly growing and was bigger than the last time. Tumor growth was controlled with antiangiogenesis inhibitor; IV bevacizumab and high dose steroids and opioids for pain. After four months, we could not continue bevacizumab due to very high blood pressure and the patient died while waiting for palliative surgery. Childhood fibrosarcoma, including IFS, has classically been treated with surgery alone or with neoadjuvant chemotherapy and surgery. In cases that are not amenable, surgical resection is done upfront. Patients with IFS have an excellent prognosis, with survival rates of more than 90% in some series. A multidisciplinary approach is essential in managing infantile fibrosarcoma as it has a high potency of recurrence during teenage or later in life with malignant transformation. This could have been prevented when the clinicians are well aware of this risk of recurrence and primary surgery has to be planned very carefully with multidisciplinary involvement.

PubMed: 33604210
DOI: 10.7759/cureus.12672

Authors: A Ferrari, G Bisogno, M Casanova...

BACKGROUND

Only a few reports on the clinical features and management of childhood leiomyosarcoma are available. To contribute additional information on the management of this rare tumor, we report on a series of 16 pediatric patients treated from 1982 to 1998 by the Soft Tissue Sarcoma Italian Cooperative Group.

PATIENTS AND METHODS

Primary surgery was conservative in all but two patients, and consisted of biopsy--three cases, non-radical excision--four, and radical resection--nine (involving a primary re-excision in 4 of 9). In two cases secondary radical surgery was performed after primary chemotherapy. Chemotherapy was administered to 9 of 16 patients, radiotherapy to three.

RESULTS

After a median follow-up of seven years (range 3-18), the five-year event-free survival (EFS) and overall survival were 56.3% and 72.9%, respectively; 12 of 16 patients were alive (nine of them in continuos complete remission). Univariate analysis was performed to compare EFS according to different subgroups: size represented the most significant prognostic factor.

CONCLUSIONS

Complete surgical resection is the mainstay of treatment for leiomyosarcoma. The role of both adjuvant chemotherapy and radiotherapy has yet to be established, and awaits cooperative multicentric studies.

Topics: Adolescent; Adult; Child; Child, Preschool; Disease-Free Survival; Female; Follow-Up Studies; Humans; Italy; Leiomyosarcoma; Male; Survival Analysis

PubMed: 11583201
DOI: 10.1023/a:1011676813582